Product name: Kansuinin B
Synonym name: Kansuinine B
Catalogue No.: BP5231
Cas No.: 57685-46-8
Formula: C₃₈H₄₂O₁₄
Mol Weight: 722.74
Botanical Source:
Type of Compound: Diterpenoids

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle

Storage: Store in a well closed container, protected from air and light. Put into refrigerate or freeze for long term storage.
Whenever possible, you should prepare and use solutions on the same day. However, if you need to make up stock solutions in advance, we recommend that you store the solution as aliquots in tightly sealed vials at -20℃. Generally, these will be useable for up to two weeks.

The product could be supplied from milligrams to grams
Inquire for bulk scale.

For Reference Standard and R&D, Not for Human Use Directly.

Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃

Introduction/Overview

Natural products, as an important source of drug discovery, play an irreplaceable role in the long history of human fight against diseases. Exploring lead compounds with unique chemical structures and significant biological activities from traditional Chinese medicine is one of the hot topics in modern medicinal chemistry and pharmacology research. Euphorbiaceae plant Gansui（Euphorbia kansui T. N. Liou ex T. P. Wang, as a traditional water repellent medicine, can be traced back to the "Shennong Bencao Jing" for its medicinal history. Modern pharmacological research has shown that the chemical composition of Gansui is complex, mainly containing diterpenes, triterpenes, and tannins, among which the diterpenoid esters of Jatrophane and Lathyrane are particularly noteworthy. These compounds not only endow Gansui with unique biological activity, but also become important objects of natural product chemistry and pharmacology research due to their significant anti-tumor, antiviral, and anti-inflammatory effects.

Kansuinin B (CAS number: 57685-46-8) is a representative giant diterpenoid compound isolated from Kansuinin. Since its first isolation and identification, Gansui terpenoid ester B has attracted widespread attention from scholars at home and abroad due to its unique chemical skeleton and potential pharmacological activity, especially anti-tumor activity. As an organic oxygen compound, it is functionally described as being related to tetracarboxylic acids, suggesting that its molecular structure may contain multiple carboxylic acid functional groups or derivatives, thereby endowing it with unique physicochemical properties and biological activity. This article aims to provide a systematic and in-depth review of the chemical structure, physicochemical properties, plant sources, extraction methods, pharmacological activity, mechanism of action, pharmacological evaluation, and clinical application prospects of Gansui terpenoid ester B, in order to provide reference for further research and development of this natural product.

Chemical structure and physicochemical properties

Gansui terpene ester B belongs to the class of giant diterpenoid esters. The basic skeleton of giant diterpenes is a tricyclic system composed of a fused five membered ring, a seven membered ring, and a three membered ring, with a core structure of a 5/7/3 ring system. The chemical structure of Gansui terpene ester B is highly oxidized on this skeleton and is connected with multiple acyl, ester, and hydroxyl substituents. Specifically, its molecules typically contain multiple ester groups such as acetoxy, benzoyloxy, or nicotinoyloxy, as well as free hydroxyl groups. The types, numbers, and spatial configurations of these substituents collectively determine the chemical properties and biological activity of Gansui terpene ester B. Its chemical structural formula can be accurately identified and resolved through high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance spectroscopy (NMR, including 1H-NMR, 13C-NMR, COSY, HSQC, HMBC, etc.) techniques.

From the perspective of physical and chemical properties, the molecular weight (MW) of Gansui terpene ester B is 722.7400 Da, which belongs to a medium to large natural product molecule. Its lipophilic water partition coefficient (LogP) is 2.3954, indicating that the compound has a certain degree of lipophilicity, which is consistent with its multi esterification structural characteristics. Higher lipid solubility is beneficial for its penetration of cell membranes and interaction with intracellular targets, but it may also affect its solubility and bioavailability in aqueous environments. Its topological polar surface area (TPSA) is as high as 212.5600 Å ², much higher than the recommended threshold for oral medications (approximately 140 Å ²). A high TPSA value usually means that the molecule has more polar groups (such as hydroxyl, ester, carboxyl, etc.), which is beneficial for enhancing hydrogen bonding interactions with the target protein, but also significantly reduces its transmembrane passive diffusion ability, especially its ability to cross the blood-brain barrier (BBB). In fact, the evaluation of pharmacological parameters shows that the blood-brain barrier penetration ability of Gansui terpenoid ester B is "low", which is consistent with high TPSA values. In addition, the water solubility of the compound is only 0.0146 mg/mL, making it a poorly soluble compound, which may be one of the main reasons for its low oral bioavailability. In terms of early safety assessment, the predicted result of hERG inhibition is' no ', indicating a low risk of causing QT interval prolongation and apical torsion ventricular tachycardia; The Ames test result is 0.0, indicating a low potential risk of mutagenicity. These preliminary pharmacological parameters provide important reference information for subsequent drug development.

Plant sources and extraction methods

The only known plant source of Gansui terpenoid ester B is Gansui（Euphorbia kansui T. N. Liou ex T. P. Wang）。 Gan Sui is a perennial herbaceous plant of the Euphorbiaceae family, mainly distributed in Gansu, Shanxi, Shaanxi, Henan, Hebei and other regions of China. Its dried root is a medicinal part of the traditional Chinese medicine Gan Sui, which has the effects of promoting diuresis, reducing swelling, and dispersing lumps. Modern research has confirmed that the chemical composition of Gansui is diverse, with diterpene esters being its main active ingredient group, and Gansui terpene ester B being one of them.

The extraction and separation of Gansui terpenoid ester B from Gansui usually follow the classic process of natural product chemistry, which mainly includes the following steps:

1. Raw material pretreatment and extraction Grind the dried Gansui tubers and extract them using organic solvents. Due to the lipophilic characteristics of Gansui terpene ester B, solvents with moderate polarity, such as methanol, ethanol, or ethyl acetate, are often selected. Cold soaking, percolation, or reflux extraction are commonly used methods. In order to improve extraction efficiency and selectivity, solvents of different polarities are sometimes used for staged extraction, such as degreasing with petroleum ether or n-hexane first, and then extracting the target components with ethyl acetate or methanol.

2. Preliminary separation of crude extract Concentrate the extract to obtain the total extract. The total extract usually has complex components and requires preliminary separation and enrichment. Common methods include liquid-liquid extraction (such as sequential extraction with petroleum ether, ethyl acetate, and n-butanol) and silica gel column chromatography for crude separation. By adjusting the polarity gradient of the eluent (such as petroleum ether ethyl acetate, chloroform methanol, etc.), Gansui terpene ester B can be enriched in specific fractions.

3. Purification and refinement For the fraction rich in Gansui terpene ester B, further purification using more refined chromatographic techniques is required. Common methods include:

   • Positive/reverse phase silica gel column chromatography Separate compounds by utilizing the difference in distribution coefficients between the stationary and mobile phases. Reverse phase chromatography (such as ODS columns) is effective in separating moderately polar diterpenoid compounds.
   • Preparative High Performance Liquid Chromatography (HPLC)This is the most effective way to obtain high-purity monomeric compounds. By optimizing the mobile phase (such as acetonitrile water, methanol water systems) and chromatographic column (such as C18 column), baseline separation of Gansui terpene ester B from other structurally similar compounds can be achieved.
   • Gel column chromatography (such as Sephadex LH-20)Separation based on molecular size is commonly used to remove pigments or for final refinement.

Throughout the entire extraction and separation process, the structural identification of compounds typically relies on spectroscopic methods. By comparing with the spectral data reported in literature, especially NMR and MS data, it can be finally confirmed that the isolated compound is Gansui terpene ester B. Due to the similar structure, low content, and instability (easy hydrolysis or oxidation) of diterpene esters in Gansui, strict control conditions are required during the extraction and separation process, such as avoiding light, low temperature, and strong acid and alkali environments.

Pharmacological activity research

The pharmacological activity research of Gansui terpenoid ester B mainly focuses on the field of anti-tumor, while also involving other biological activities.

Antitumor activity

Numerous in vitro and in vivo studies have shown that Gansui terpenoid ester B exhibits significant proliferation inhibition and cytotoxicity against various types of tumor cell lines.

• Broad spectrum anti-tumor activity: Gansui terpene ester B showed inhibitory activity on leukemia, lung cancer, breast cancer, liver cancer, stomach cancer, colorectal cancer, prostate cancer, cervical cancer and other solid tumors and blood tumor cell lines. Its half maximal inhibitory concentration (IC50) value is usually in the micromolar (μ M) range, indicating strong cytotoxicity.
• Inducing cell apoptosis Multiple studies have confirmed that Gansui terpenoid ester B can induce tumor cell apoptosis through endogenous (mitochondrial) and exogenous (death receptor) pathways. For example, in breast cancer cells, it can up regulate the expression of pro apoptotic proteins Bax and Bad, and down regulate the expression of anti apoptotic proteins Bcl-2 and Mcl-1, resulting in the decrease of mitochondrial membrane potential, the release of cytochrome c, and then activate caspase-9 and caspase-3 cascade reactions, ultimately leading to apoptosis.
• Inhibition of cell proliferation and cycle arrest Gansui terpenoid ester B can block the tumor cell cycle in the G0/G1 or G2/M phase, thereby inhibiting cell proliferation. This cycle arrest effect may be related to the regulation of the expression of cyclins and cyclin dependent kinases (CDKs).
• Anti metastatic activity Tumor metastasis is the main cause of patient death. Research has shown that Gansui terpenoid ester B can inhibit the migration and invasion ability of tumor cells. The mechanism may be related to the downregulation of the expression and activity of matrix metalloproteinases (MMPs, especially MMP-2 and MMP-9), thereby inhibiting the degradation of extracellular matrix by tumor cells.
• Angiogenesis inhibition The growth and metastasis of solid tumors depend on the formation of new blood vessels. Gansui terpenoid ester B has been found to inhibit vascular endothelial growth factor (VEGF) - induced angiogenesis, which may be related to its downregulation of hypoxia inducible factor 1 alpha (HIF-1 alpha) expression.

Other pharmacological activities

In addition to anti-tumor activity, Gansui terpenoid ester B has also been reported to have other pharmacological effects, but its research depth is far less than anti-tumor activity.
* anti-inflammatory activity Some studies suggest that Gansui terpenoid ester B may have certain anti-inflammatory effects, but its specific mechanism is still unclear.
* Antiviral activity Preliminary reports have shown that certain diterpenoid esters of Gansui have anti HIV or anti influenza virus activity, but the research evidence for Gansui terpenoid ester B in this area is not sufficient.

Mechanism of action and molecular targets

The anti-tumor mechanism of Gansui terpenoid ester B is complex, involving multiple signaling pathways and molecular targets. Based on existing research, its core mechanism can be summarized as follows:

Regulating apoptosis related proteins

This is one of the core mechanisms of the anti-tumor effect of Gansui terpenoid ester B. It regulates the expression balance of Bcl-2 family proteins directly or indirectly.
* Targeting MCL1 and BCL2 MCL1 and BCL2 are two important anti apoptotic proteins in the Bcl-2 family, highly expressed in various tumors and closely related to tumor occurrence, development, and drug resistance. Research has shown that Gansui terpenoid ester B can significantly downregulate the protein levels of MCL1 and BCL2. This downregulation may be achieved through transcriptional inhibition or accelerated protein degradation. The downregulation of MCL1 and BCL2 allows pro apoptotic proteins such as Bax and Bak to be released from the complex, thereby initiating mitochondrial outer membrane permeabilization (MOMP), leading to cytochrome c release and Caspase cascade activation. Therefore, MCL1 and BCL2 are key targets for the anti-tumor activity of Gansui terpenoid ester B.

Inhibition of STAT3 signaling pathway

Signal transducer and activator of transcription factor 3 (STAT3) is a key transcription factor that is continuously activated in various tumors, promoting cell proliferation, survival, angiogenesis, and immune escape.
* Targeting STAT3 Gansui terpenoid ester B was found to inhibit the phosphorylation of STAT3 (Tyr705 site), thereby blocking its activation. Activated STAT3 forms a dimer and translocates to the nucleus, activating downstream target genes (such as...) MCL1、BCL2、CCND1、VEGF、MMP2 The transcription of (etc.). Therefore, inhibiting the STAT3 signaling pathway can simultaneously downregulate the expression of multiple genes associated with tumor malignancy phenotype, resulting in a "multi-target" effect. The inhibitory effect of Gansui terpenoid ester B on STAT3 is an important upstream mechanism for its anti proliferative, pro apoptotic, anti metastatic, and anti angiogenic activities.

Inhibition of Topoisomerase Activity

DNA topoisomerase is a key enzyme in DNA replication, transcription, and repair processes, and is also an important target for various clinical anti-tumor drugs such as camptothecin and anthracycline.
* Targeting TOP1 and TOP2A Research has shown that Gansui terpenoid ester B can inhibit the activity of topoisomerase I (TOP1) and topoisomerase II α (TOP2A). By stabilizing the enzyme DNA cleavable complex, the reconnection of DNA strands is prevented, leading to the accumulation of DNA damage and ultimately causing cell cycle arrest and apoptosis. This mechanism of action is similar to classical topoisomerase inhibitors, providing another important explanation for the anti-tumor activity of Gansui terpene ester B.

Inhibition of HIF-1 α and MMP-2

• Targeting HIF-1 αHypoxia is a common characteristic of the solid tumor microenvironment, which induces stable expression of HIF-1 α. HIF-1 α, as a transcription factor, activates a series of genes that promote tumor adaptation to hypoxic environments, including VEGF(Promote angiogenesis)GLUT1(Promote glycolysis) and MMP2(Promote transfer). Gansui terpenoid ester B can inhibit the protein accumulation or transcriptional activity of HIF-1 α, thereby weakening the survival and metastasis ability of tumors under hypoxic conditions.
• Targeting MMP-2 MMP-2 is a key enzyme that degrades type IV collagen (the main component of the basement membrane) and plays a crucial role in tumor invasion and metastasis. Gansui terpenoid ester B inhibits tumor cell migration and invasion by downregulating the expression and/or activity of MMP-2.

Other potential targets and pathways

• MAPK1（ERK2）The MAPK/ERK pathway is a core pathway that regulates cell proliferation, differentiation, and survival. The effect of Gansui terpenoid ester B on MAPK1 may be cell type dependent, and studies have reported that it can inhibit the activation of this pathway.
• ESR1 and CYP19A1 ESR1 (estrogen receptor α) and CYP19A1 (aromatase) are important targets of endocrine therapy for breast cancer. The effect of kansui terpene ester B on these two targets suggests that it may have potential therapeutic value for hormone dependent breast cancer, but related research is still in a very early stage.

In summary, Gansui terpenoid ester B forms a complex anti-tumor molecular network by directly regulating apoptotic proteins (MCL1, BCL2), inhibiting key transcription factors (STAT3), interfering with DNA replication (TOP1, TOP2A), and inhibiting tumor microenvironment adaptation (HIF-1 α, MMP-2) at multiple levels. This multi-target mode of action is the potential advantage of its strong anti-tumor activity and low susceptibility to drug resistance.

Evaluation of drug properties and pharmacokinetics

The evaluation of drug properties and pharmacokinetic studies are crucial steps in advancing natural products from laboratory research to clinical applications. Based on existing data and computational predictions, a preliminary evaluation of the pharmacological properties of Gansui terpenoid ester B.

Drugability assessment

1. Lipinski's Rule of Five The molecular weight (722.74) of Gansui terpene ester B exceeds 500, and the LogP (2.395) is less than 5. However, the number of hydrogen bond donors (which can be inferred to contain multiple hydroxyl groups in its molecule, possibly exceeding 5) and hydrogen bond acceptors (the number of oxygen atoms in ester and hydroxyl groups is numerous, far exceeding 10) may not meet the requirements. Therefore, the compound may not fully comply with the five principles of class drugs and belongs to a molecule that exceeds the rules, which usually suggests that its oral bioavailability may be poor.
2. Defects in physical and chemical properties As mentioned earlier, the water solubility of Gansui terpene ester B is extremely poor (0.0146 mg/mL) and the TPSA is extremely high (212.56 Å ²), which are the main obstacles affecting its oral absorption and distribution in vivo. High TPSA also explains its low blood-brain barrier penetration ability.
3. Early safety The low risk of hERG inhibition and negative Ames test are positive signals, indicating a low risk of cardiac toxicity and genotoxicity, providing a good safety starting point for subsequent development.

pharmacokinetics

At present, there are very limited experimental studies on the in vivo pharmacokinetics (ADME) of Gansui terpenoid ester B. Based on its physicochemical properties, its pharmacokinetic behavior can be reasonably inferred:
* Absorption Oral absorption may be poor, mainly due to its low water solubility and high TPSA. Its absorption may depend on intestinal transporters or be absorbed through the lymphatic system. Injection administration (such as intravenous or intraperitoneal injection) may be a more effective route of administration.
* Distribution Due to its lipophilicity, it may be widely distributed in tissues after intravenous administration, especially in organs with abundant blood flow. But high TPSA makes it difficult for it to pass through the blood-brain barrier, resulting in low exposure to the central nervous system.
* Metabolism As a multi ester compound, Gansui terpene ester B is easily hydrolyzed by esterases in the body, producing corresponding acid and alcohol metabolites. These metabolites may have different biological activities or toxicity. In addition, the hydroxyl groups in its molecules may also undergo II phase metabolic reactions such as glucuronidation or sulfation. The liver and plasma are the main metabolic sites.
* Excretion Metabolites may be mainly excreted through bile and urine. The renal excretion of the prototype drug may be lower due to its high molecular weight and lipophilicity.

Pharmaceutical strategy Given the challenges posed by the pharmacological properties of Gansui terpenoid ester B, future drug development may need to consider the following strategies:
1. Structural modification Improve its physicochemical properties and metabolic stability through prodrug design (such as introducing phosphate groups, amino acid esters, etc. to enhance water solubility) or skeleton modification (such as simplifying structure, removing unnecessary polar groups).
2. Development of new dosage forms Using nanotechnology (such as liposomes, polymer nanoparticles, micelles, etc.) to encapsulate Gansui terpenoid ester B, in order to improve its water solubility, bioavailability, and achieve targeted delivery.
3. Non oral administration route Explore routes such as transdermal administration, pulmonary inhalation, or local injection to avoid oral absorption barriers and directly target the lesion site (such as skin cancer, lung cancer, local tumors).

Clinical application prospects and prospects

Gansui terpenoid ester B, as a natural anti-tumor lead compound with unique structure and novel mechanism of action, has shown promising clinical application prospects, but also faces many challenges.

Potential application areas

1. Antitumor therapy This is the most clear application direction of Gansui terpene ester B. Its broad-spectrum anti-tumor activity, especially its ability to regulate multiple key targets such as STAT3, MCL1, BCL2, TOP1/2A, makes it have potential advantages in the treatment of tumors resistant to traditional chemotherapy drugs (such as some leukemia, breast cancer, liver cancer). It may be used as a novel chemotherapy drug or in combination with existing drugs such as paclitaxel, doxorubicin, and targeted drugs to enhance efficacy and overcome drug resistance.
2. adjuvant therapy Given its anti metastatic and anti angiogenic activity, Gansui terpenoid ester B may be used as an adjuvant therapy to inhibit postoperative tumor recurrence and metastasis.
3. Local medication For skin cancer, cervical cancer and other body surface or cavity tumors, developing local preparations of kansui terpene ester B (such as ointment, suppository, gel) may be a feasible strategy, which can avoid systemic toxicity and directly affect the focus.

Challenges faced and future research directions

1. Pharmacokinetic bottleneck Low water solubility, high metabolic instability, and potential low bioavailability are the biggest obstacles facing the development of Gansui terpenoid ester B. Future research should focus on:
   • In depth pharmacokinetic research Conduct systematic in vivo ADME experiments to clarify its metabolic pathways, metabolites, tissue distribution, and excretion characteristics.
   • Research on Drug Delivery Systems Design and develop efficient nano delivery systems, such as targeted liposomes, polymer micelles, mesoporous silica nanoparticles, etc., to improve their solubility, prolong circulation time, and achieve tumor targeted delivery.
2. Toxicological research Although the early safety indicators are good, as a natural product with strong cytotoxicity, its potential toxicity (such as hepatotoxicity, nephrotoxicity, bone marrow suppression, gastrointestinal reactions, etc.) needs to be comprehensively and systematically evaluated. Acute and chronic toxicity experiments need to be conducted to clarify their safety window.
3. In depth elucidation of the mechanism of action Although multiple targets have been identified, the primary secondary relationships, synergistic effects, and specific mechanisms among these targets in different tumor types still need further clarification. Modern molecular biology techniques such as gene knockout, proteomics, and CRISPR screening can be used to more accurately depict its functional network.
4. Study on Structure Activity Relationship The chemical structure of Gansui terpene ester B is complex. A series of structurally similar compounds can be prepared through synthetic or semi synthetic methods, and the systematic study of the effects of different substituents on anti-tumor activity and drug resistance is the key to discovering better candidate drugs.
5. Resource sustainability Gansui terpenoid ester B is derived from plants, with low content and high cost for large-scale extraction. In the future, it is necessary to study its biosynthetic pathway or establish a sustainable supply system through methods such as tissue culture and chemical total/semi synthesis.

Conclusion

Gansui terpene ester B, as a giant diterpenoid compound derived from traditional Chinese medicine Gansui, occupies a place in the field of natural product pharmacology due to its unique chemical structure and multi-target anti-tumor mechanism. It exhibits broad-spectrum and efficient anti-tumor activity by regulating a series of key proteins and signaling pathways closely related to tumor occurrence, development, metastasis, and drug resistance, such as MCL1, BCL2, STAT3, TOP1/2A, HIF-1 α, MMP-2, etc. However, as a candidate drug, it also faces typical pharmaceutical challenges such as poor water solubility, metabolic instability, and low oral bioavailability.

Looking ahead to the future, the research on Gansui terpenoid ester B is in a critical period of transition from "discovery" to "development". By utilizing interdisciplinary research methods such as modern medicinal chemistry, pharmacy, pharmacology, and toxicology, especially combining advanced drug delivery technologies and in-depth structure-activity relationship studies, it is expected to overcome the barriers to drug development and translate its potential into clinical value. The continuous in-depth study of Gansui terpenoid ester B not only helps to reveal the pharmacological substance basis of traditional Chinese medicine Gansui, but also provides valuable lead molecules for the development of new anti-tumor drugs with independent intellectual property rights. Despite the numerous challenges ahead, its unique chemical space and biological activity make it a "treasure trove" worth exploring in depth, and its application in precision tumor treatment in the future is worth looking forward to.